PROJECT SUMMARY: Acute Respiratory Distress Syndrome (ARDS) is a devastatingly intense lung inflammatory disorder that annually afflicts more than 1 million individuals world-wide (200,000 cases/year in the U.S.) with an unacceptable mortality rate of 30-40%. Substantial clinical and biological heterogeneity within ARDS phenotypes has greatly impeded therapeutic developments to reduce mortality. All therapies currently employed in ARDS management are ge- neric. The critical care community suffers from a lack of tools that allow identification of ARDS sub-phenotypes and individuals most likely to benefit from novel therapies. Recently, the hyperinflammatory and low inflammatory ARDS sub-phenotypes were identified that markedly differ in natural histories, clinical and biological character- istics, biomarker profiles, responses to positive end-expiratory pressure, ventilator- and organ failure-free days and mortality. ARDS severity (PaO2/FiO2 ratio), the severity of renal or hepatic failure, or the extent of leukocy- tosis failed to distinguish the two phenotypes. As the mortality of the hyperinflammatory phenotype is 3-5 times greater than low inflammatory phenotype, this Phase I STTR will leverage substantial complementary expertise to: i) establish a novel panel of ARDS biomarkers (CRIT-ICU Panel) that stratifies subjects at risk for ARDS into high and low mortality sub-phenotypes; and ii) develop a quantitative platform to allow assessment of these validated biomarkers upon patient entry into the ER or ICU. Our preliminary biomarker data are strong and include 11 ARDS-relevant plasma biomarkers in >250 well-phenotyped ARDS subjects and 70 controls. The targeted biomarkers include cytokine-chemokines (IL-6, IL-8, IL-1b, IL-RA), dual-functioning cytozymes i.e. cy- tokine/intracellular enzymes (macrophage migration inhibitory factor, NAMPT), vascular injury markers (VEGF- A, S1PR3, angiopoietin 2), and the advanced glycosylation end product pathway (HMGB1, soluble RAGE). Spe- cific Aim #1 will apply standard biostatistical approaches as well as novel neural network artificial intelligence analysis of this existing dataset to identify an optimal plasma-derived CRIT-ICU Panel which predicts ICU mor- tality in patients with sepsis or trauma who are at risk for development of respiratory failure and ARDS. Specific Aim #2 will develop an optimized and highly standardized Predictive Platform for the CRIT-ICU biomarkers iden- tified to be used in the clinical care setting. Finally, Specific Aim #3 will conduct retrospective validation studies of the optimized CRIT-ICU Panel in biobanked samples from 2 large cohorts: an emergency room-ARDS cohort (PETAL Clinical Network, n=800) and a Spanish sepsis-ARDS cohort (n=200). We speculate that unique exper- tise within Aqualung Therapeutics Corp., PAI Life Sciences Inc., InBios International Inc. and the University of Arizona Health Sciences will drive future prospective validation of the CRIT-ICU Panel in patients at risk for ARDS (Phase II STTR) and lead to development of a true Point of Care test to accelerate clinical trial stratification strategies, and development of innovative ARDS therapeutics to reduce mortality in this devastating syndrome.